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Originally published as JCO Early Release 10.1200/JCO.2008.17.2742 on December 8 2008 © 2009 American Society of Clinical Oncology. Early Prediction of Response to Sunitinib After Imatinib Failure by 18F-Fluorodeoxyglucose Positron Emission Tomography in Patients With Gastrointestinal Stromal Tumor
From the Nuclear Medicine, Pathology, and Medical Oncology Departments, Centre Hospitalier Universitaire Vaudois and University of Lausanne, Lausanne, Switzerland Corresponding author: John O. Prior, MD, PhD, Rue du Bugnon 46, Lausanne, Switzerland CH-1011; e-mail: John.Prior{at}chuv.ch
Purpose Positron emission tomography with 18F-fluorodeoxyglucose (FDG-PET) was used to evaluate treatment response in patients with gastrointestinal stromal tumors (GIST) after administration of sunitinib, a multitargeted tyrosine kinase inhibitor, after imatinib failure. Patients and Methods Tumor metabolism was assessed with FDG-PET before and after the first 4 weeks of sunitinib therapy in 23 patients who received one to 12 cycles of sunitinib therapy (4 weeks of 50 mg/d, 2 weeks off). Treatment response was expressed as the percent change in maximal standardized uptake values (SUV). The primary end point of time to tumor progression was compared with early PET results on the basis of traditional Response Evaluation Criteria in Solid Tumors (RECIST) criteria. Results Progression-free survival (PFS) was correlated with early FDG-PET metabolic response (P < .0001). Using –25% and +25% thresholds for SUV variations from baseline, early FDG-PET response was stratified in metabolic partial response, metabolically stable disease, or metabolically progressive disease; median PFS rates were 29, 16, and 4 weeks, respectively. Similarly, when a single FDG-PET positive/negative was considered after 4 weeks of sunitinib, the median PFS was 29 weeks for SUVs less than 8 g/mL versus 4 weeks for SUVs of 8 g/mL or greater (P < .0001). None of the patients with metabolically progressive disease subsequently responded according to RECIST criteria. Multivariate analysis showed shorter PFS in patients who had higher residual SUVs (P < .0001), primary resistance to imatinib (P = .024), or nongastric GIST (P = .002), regardless of the mutational status of the KIT and PDGFRA genes. Conclusion Week 4 FDG-PET is useful for early assessment of treatment response and for the prediction of clinical outcome. Thus, it offers opportunities to individualize and optimize patient therapy.
Gastrointestinal stromal tumors (GISTs) are the most common soft tissue sarcomas that initiate from the gastrointestinal (GI) tract, as they originate from the interstitial cells of Cajal with activated KIT or PDGFRA mutations.1-3 Treatment of localized GIST is primarily surgical, and complete resection can be accomplished in 40% to 60% of patients; metastases to the liver and peritoneum are common. Chemotherapy and radiotherapy are ineffective. Metastatic GISTs have a poor prognosis, although the introduction of the tyrosine kinase inhibitor imatinib mesylate (Gleevec, Glivec; Novartis, East Hanover, NJ)4 has dramatically improved tumor control (80% of patients experience objective response or disease stability), progression-free survival (PFS; median, 20 to 26 months), and overall survival (OS; median, 51 to 57 months) of patients with overt metastatic disease.5,6 However, more than half of the patients will show tumor progression within 2 years of initiating imatinib therapy, most often because of lesions with secondary additional mutations.7,8 Some patients will show a second response after the daily imatinib dose is increased.9 Nevertheless, progression after imatinib therapy is generally associated with poor outcome, and patients often die within a few months.5 Recently, sunitinib maleate (Sutent; Pfizer, New York, NY), a novel, multitargeted tyrosine kinase inhibitor (KIT, PDGFRA, PDGFRB, VEGFR1 to VEGFR3, and FLT3), has been approved for patients with imatinib-resistant, progressive disease. Sunitinib, when given to patients after imatinib failure, increased the median PFS approximately fourfold compared with placebo (27 v 6 weeks; P < .0001) and was associated with greater OS (hazard ratio, 0.49; P = .007).10 Changes in tumor glucose utilization on the basis of 18F-flurodeoxyglucose (FDG) positron emission tomography (PET; FDG-PET) shortly after initiation of treatment has been shown to correlate with patient outcome in imatinib-treated patients with GIST.11,12 Quantitative change in FDG uptake was an early predictor of response to imatinib and can be used for early assessment of treatment response.13-18 This may allow for rapid initiation of alternative strategies and minimization of potential adverse effects of ineffective therapy, which may lead to individually adapted and optimized treatment strategies.19,20 The predictive power of early FDG-PET for patients who undergo salvage treatment with sunitinib after imatinib failure has not been investigated. Extrapolation of the observations in first-line treatment with imatinib may not be appropriate, as differences in cellular mechanisms might be involved. Molecular classification of specific mutations that affect the KIT or PDGFRA genes may potentially guide the choice of the most appropriate inhibitor.20-22 Until then, metabolic imaging may be the only means for early evaluation of treatment efficacy. The goal of this study is to prospectively evaluate FDG-PET in patients with advanced imatinib-resistant GIST treated with sunitinib for early prediction of response and outcome to targeted therapy.
Patients Patients who received sunitinib salvage therapy as part of two identical clinical protocols (ie, phase III, randomized study NCT00075218 [ClinicalTrials.gov] ; expanded access protocol NCT00094029 [ClinicalTrials.gov] )10,23 were deemed eligible for this ancillary imaging study. All eligible patients were  18 years old, had histologically proven GIST (ie, measurable disease 20 mm size on computed tomography [CT]), and had aborted previous imatinib therapy because of recent tumor progression or unacceptable imatinib toxicity. All patients had an Eastern Cooperative Oncology Group (ECOG) performance status less than two. Sutinib therapy was started at least 1 week after the final imatinib dose or after resolution of all imatinib-related toxicity. The study protocol was approved by the local ethics committee and Swiss regulatory authorities, and all patients gave written informed consent.
Treatment
Molecular Classification
FDG-PET
Response Assessment and Outcome
Statistical Analysis
Patients Between June 2004 and June 2006, 24 patients were enrolled and received sunitinib for recurrent or progressive GIST. All patients had distant metastases without local recurrence. Twenty-three patients had undergone early FDG-PET evaluation (mean age with standard deviation, 52 ± 16 years; range, 24 to 76 years); one patient was excluded, as postsunitinib FDG-PET could not be performed for logistical reasons. Detailed patient characteristics are listed in Table 1. Patients received a median of five cycles of sunitinib (range, one to 12 cycles; interquartile range [IQR], two to seven cycles). Sunitinib administration was discontinued after 30 weeks in one patient because of cardiac failure with fatal outcome and was temporarily interrupted after 24 weeks in one patient for causes unrelated to sunitinib (GI tract hemorrhage from pre-existing stomach ulcer and resection of a colonic stenosis because of diverticulitis). The sunitinib dose was also temporarily reduced in three patients because of grade 3 hypertension (one with additional thrombocytopenia) or hand-foot skin reaction (one patient) and was given continuously (37.5 mg/d) in one long-term responder (19 months) because of recurrent pain during off-drug periods after cycle 4. Baseline FDG-PET was performed at a median of 5 days (IQR, 1 to 9 days) before starting sunitinib. At that time, all patients had been off imatinib for at least 7 days (median, 12 days; IQR, 9 to 22 days). Early PET response evaluation was performed at the end of week 4 of cycle 1 in 21 patients and after cycle 2 in two patients. PET acquisitions were performed while patients were still receiving the last dose of sunitinib.
Patient Follow-Up After a follow-up that ranged up to 25 months, all 23 patients had progressed, and 20 (87%) of 23 had died. The median PFS was 6.2 months (95% CI, 3.6 to 7.8), and the median OS was 14 months (95% CI, 8 to 20). The proportion of patients without progression at 3 months was 61%, although it decreased to 52% at 6 months and 13% at 12 months. The proportion of patients who still received sunitinib was 74% at 3 months, 57% at 6 months, and 17% at 12 months.
PET Assessment of Therapeutic Response
Metabolic Response and PFS PFS correlated significantly with early FDG-PET metabolic response (Table 2; Fig 1B). Patients with metabolic partial response after a 4-week sunitinib treatment had prolonged PFS compared with patients with metabolically stable disease (P = .046) or patients with metabolically progressive disease (P < .0001). PFS was also significantly longer in patients with metabolically stable disease compared with metabolically progressive disease (P = .010). Importantly, all patients with metabolically progressive disease at early PET assessment were subsequently confirmed to have experienced progression by RECIST criteria. Clinical benefit (ie, no progression for 6 months) was observed in 11 (48%) of 23 patients.
In the clinical setting, imatinib washout may not always be completed before scheduling baseline FDG-PET, or patients may need treatment before a baseline PET can be performed. Therefore, we also investigated whether an early metabolic assessment with a single postsunitinib FDG-PET scan after one cycle would provide any useful prognostic information. We defined an SUV threshold of 8 g/mL (which corresponded to the average SUV observed on the second PET [ie, 7.7 ± 4.4] rounded to the nearest integer) to separate responders (ie, SUV < 8) from poor responders (ie, SUV 8). There was a significant association between residual FDG tumor uptake by PET after one course of sunitinib and PFS (P < 0.0001; Table 2; Fig 2A).
Mutation Analysis of KIT and PDGFRA Genes Results of mutational analysis of KIT and PDGFRA genes in primary tumor specimens or metastases at diagnosis are listed in Table 1; in one patient, the available biopsy material was insufficient in quantity for this analysis. The majority of the patients presented with mutation of the KIT gene (73%); the exon 11 mutation was the most frequent (41%), whereas no patient presented with PDGFRA gene mutations. There was no correlation between KIT gene mutations and PFS or OS, clinical benefit, PET baseline SUV, or the baseline SUV change in response to sunitinib (all P > .35).
Prediction of PFS On multivariate analysis that used only one postsunitinib PET, the residual SUV was the most powerful and independent predictor of PFS (P < .0001; Table 3) and was followed by the gastric localization of primary GIST (P = .002) and by primary imatinib resistance (P = .024). In both baseline and post-therapy PET studies, multivariate analysis showed that only the PET results were independent predictors of PFS (Table 4), and better outcomes were observed for more marked SUV reduction between PET studies (P < .0001), lower residual SUV on the second PET study (P = .001), and gastric GIST (P = .038).
OS The OS was predicted by early metabolic response (Figs 2B and 2C). Median OS was 6 months (95% CI, 2 to 14) versus 17 months (95% CI, 8 to 22) in patients with residual SUV 8 versus SUV less than 8, respectively. The difference was not significant because of the confounding effect of salvage therapy in one patient with exceptionally long survival (29 months v median of 6 months) who switched early to a third-line therapy. When this patient was excluded from the analysis, the difference became highly significant (P = .004; Fig 2C).
This study shows the utility of FDG-PET for early response assessment in patients who have GIST treated with sunitinib after imatinib failure. Metabolic response to therapy, measured by changes in FDG uptake between a pretherapeutic FDG-PET scan and at 4 weeks after initiation of therapy, was strongly predictive of PFS. Importantly, a single FDG-PET study performed as early at 4 weeks after initiation of treatment predicted PFS with similar accuracy. Patients with favorable response as indicated by lower postsunitinib SUVs demonstrated longer median PFS and OS than poorly responding patients with higher SUVs. FDG-PET scan predicted clinical benefit: 79% of patients with lower residual SUVs derived a clinical benefit compared with only 13% of patients with higher SUVs. In all patients with metabolically progressive disease on PET, progression was subsequently demonstrated by RECIST criteria. In multivariate analyses, FDG-PET retained its ability to predict patient outcome and was the most significant independent predictor of PFS. The various KIT gene mutations were not correlated with clinical benefit, PFS, or OS. In patients with GIST who are treated with imatinib, the ability of FDG-PET to early predict treatment response has been shown previously by our group and others.13,15,18 PET has been significantly more accurate at the assessment of early therapeutic response compared with conventional imaging with CT and RECIST criteria.16,17,28 Adequate and early prediction of response allows for individual counseling of patients, for consideration of alternative strategies or treatments, and for less stringent clinical and imaging follow-up. A strong rationale exists to use FDG-PET for the early prediction of tumor response to protein kinase inhibitors,29-31 as many signaling pathways also have a well-established role in the regulation of tumor glucose metabolism. Importantly, the metabolic assessment by FDG-PET is always done at the end of a treatment cycle while patients are still on treatment, as a rebound increase in FDG uptake has been observed during the off period.32 A rigorous, standardized approach in patient preparation (ie, fasting period, hydration, blood glucose), image acquisition (ie, FDG uptake time, scanner quality control), and region of interest determination is needed for reproducible results and for FDG-PET to be a valid surrogate end point for treatment efficacy, as emphasized by recent guidelines.25 The multivariate analysis showed predictive value regarding GIST localization and primary resistance to imatinib. Gastric GISTs are known to have a more favorable outcome and about half the mortality compared with those that initiate in the small intestine or colon and small intestine, which tend to be larger and more aggressive than gastric ones. This may explain our observations.1-3,33 We also found a shorter PFS in patients with primary imatinib resistance that may be related to differences in mutations and, therefore, conformation or structure of the KIT or PDGFRA receptor proteins, because imatinib failure often is linked to the clonal expansion of imatinib-resistant, KIT receptor–carrying cells.34 OS was predicted by early PET metabolic response, with the exception of one patient who was rapidly switched to a third-line therapy. This stresses the importance of initiating an effective salvage therapy early and of using PET as a tool that may facilitate treatment individualization on the basis of close response monitoring. Our study has some inherent limitations. It was a single-center study with a small number of patients. Therefore, PET and the other significant independent predictors of PFS, as well as the SUV threshold derived in this study, remain to be validated prospectively in a larger patient population. Partial volume effect because of limited spatial resolution may lead to FDG uptake underestimation in small or necrotic lesions, which thus reduces SUV accuracy.25 No correlation was found between response and mutational status performed at diagnosis. This might indicate that secondary mutations affected biologic behavior and treatment response once imatinib failure occurred. During this study period, new criteria for the assessment of CT in response to imatinib in patients with GIST were developed by several groups;35,36 whether these criteria would also apply to imatinib-resistant GIST is unclear and will require additional study. The assessment of metabolic response might not incur major additional costs, as one single FDG-PET performed 4 weeks after treatment start seems sufficient for the prediction of PFS and clearly discriminates distinct groups of patients. In summary, time to progression in patients with GIST after imatinib failure is less than 6 weeks on best supporting care, so early and accurate noninvasive assessment of response to sunitinib is crucial in the selection of patients who will potentially benefit from this second-line therapy. This selection would optimize clinical outcome and reduce exposure to an ineffective treatment, which would thus save time, reduce costs, and avoid toxicity. Metabolic imaging with FDG-PET on a simple protocol may allow for the assessment of treatment response as early as after the first course of targeted therapy with sunitinib, which represents an additional step toward individualized therapy. In addition, it seems to offer better prognostication than mutational analysis. Whether this approach can be used to modify patient management with the newly available second- or third-line agents remains to be evaluated in future studies and in clinical practice.
The author(s) indicated no potential conflicts of interest.
Conception and design: John O. Prior, Valerie Elsig, Serge Leyvraz Financial support: Angelika Bischof Delaloye, Serge Leyvraz Administrative support: John O. Prior, Michael Montemurro, François Luthi, Valerie Elsig, Angelika Bischof Delaloye, Serge Leyvraz Provision of study materials or patients: Michael Montemurro, Olivier Michielin, François Luthi, Jean Benhattar, Louis Guillou, Serge Leyvraz Collection and assembly of data: John O. Prior, Michael Montemurro, Maria-Victoria Orcurto, Olivier Michielin, François Luthi, Jean Benhattar, Louis Guillou, Valerie Elsig, Roger Stupp Data analysis and interpretation: John O. Prior, Michael Montemurro, Maria-Victoria Orcurto, Olivier Michielin, Jean Benhattar, Louis Guillou, Valerie Elsig, Roger Stupp, Angelika Bischof Delaloye, Serge Leyvraz Manuscript writing: John O. Prior, Michael Montemurro, François Luthi, Roger Stupp, Angelika Bischof Delaloye, Serge Leyvraz Final approval of manuscript: John O. Prior, Michael Montemurro, Maria-Victoria Orcurto, Olivier Michielin, François Luthi, Jean Benhattar, Louis Guillou, Valerie Elsig, Roger Stupp, Angelika Bischof Delaloye, Serge Leyvraz
We thank the patients for participating in this study; the nuclear medicine physicians and technologists for performing the positron emission tomography studies; and David W. Crook, MD, for editorial assistance.
published online ahead of print at www.jco.org on December 8, 2008. Supported in part by Pfizer Inc, New York, NY within the frame of two clinical studies (A6181004 and A6181036); and by the Nuclear Medicine Department, Center Hospitalier Universitaire Vaudois, Lausanne, Switzerland. J.O.P., MD, PhD, was recipient of an Academic Research Award from the Leenaards Foundation (Lausanne, Switzerland). Presented in part at the 7th Annual Meeting of the Swiss Society of Nuclear Medicine, June 1-3, 2006, Lausanne, Switzerland; and at the 53rd Annual Meeting of the Society of Nuclear Medicine, June 3-7, 2006, San Diego, CA. The study was performed within the frame of two identical clinical protocols registered at ClinicalTrial.gov under identifiers NCT00075218 [ClinicalTrials.gov] and NCT00094029 [ClinicalTrials.gov] . Authors’ disclosures of potential conflicts of interest and author contributions are found at the end of this article. Clinical trial information can be found for the following: NCT00075218 [ClinicalTrials.gov] , NCT00094029 [ClinicalTrials.gov]
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Copyright © 2009 by the American Society of Clinical Oncology, Online ISSN: 1527-7755. Print ISSN: 0732-183X
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ABSTRACT
INTRODUCTION
SUV%) was used to classify the early response as metabolically complete response (ie, uptake equivalent to background), metabolic partial response (ie, 
